Restless legs syndrome and its treatment by dopamine agonists

The restless legs syndrome (RLS) characteristically presents with an irresi stible urge to move that is most often accompanied by creeping sensations d eep in the limbs. Occasionally the upper limbs can also be affected. RLS sy mptoms occur at rest and are typically more intense at night and at bedtime . Some patients complain about involuntary leg movements, so-called periodi c limb movements (PLM), while at rest or PLM have been observed by the bed partner. Often, patients have to get out of bed several times at night, to relieve themselves of their disagreeable sensations. The prevalence of RLS is estimated to be about 5%. Up to now only three cla sses of drugs have been systematically evaluated for treatment of RLS: benz odiazepines, opioids and dopaminergic agents. The most consistent results have been obtained with dopaminergic drugs. Sev eral studies have shown that L-dopa given with a peripheral decarboxylase i nhibitor at a 10:4 ratio is effective in treating RLS. Controlled studies u sing polysomnographic recordings in a double-blind design showed that L-dop a administered at night produces a significant reduction of RLS occurring a t bedtime and of PLM, which are often associated with nocturnal arousals. I n most cases, L-dopa 100 mg, in conjunction with the decarboxylase inhibito r carbidopa or benserazide 25 mg, suppresses RLS although a rebound of PLM may be observed in the last part of the night. The two major adverse effect s frequently seen in patients treated with L-dopa are: 1. A single dose of L-dopa at bedtime decreases PLM in the first half of th e night. Owing to the short half-life of L-dopa the efficacy sometimes decr eases in the second half of the night, which makes intake of a second dose at night or a combination with slow release levodopa necessary. 2. Augmentation of symptoms which comprises an earlier onset of RLS symptom s in the evening than before treatment: appearance of symptoms during the d ay, an involvement of other body parts (i.e, the arms) or an increased seve rity. Augmentation has been observed in patients under levodopa long-term t herapy but it may develop even shortly after onset of levodopa. Augmentation is one of the limiting factors of L-dopa therapy; thus, altern ative treatment options are of major interest. In several open treatment tr ials performed with pergolide, patients reported a marked improvement of RL S symptoms including sleep problems. Mild symptoms of augmentation under pe rgolide treatment have been reported from single patients. In another 6-mon th open label trial, pergolide proved to be effective in patients who devel oped augmentation under L-dopa by relieving daytime symptoms after switchin g to pergolide. Most recently, the results of these open label trials have been replicated in a randomized, placebo-controlled, double-blind multicenter trial. Treatm ent with a single evening dose of 0.25-0.75 mg pergolide resulted in a sign ificant improvement of almost all subjective and objective parameters. Unde r pergolide, patients rated their RLS symptoms and sleep disturbances much less severe and polysomnographic recordings also revealed a significant imp rovement of all important sleep parameters. To prevent peripheral side-effe cts such as nausea or orthostatic hypotension, pergolide should be slowly u p-titrated or domperidone should be added. Under these conditions, no major side effects have been observed in treatment trials with pergolide in dosa ges up to 1.25 mg. Pergolide with a half-life of 12-16 h thus appears to be an appropriate dru g in the therapy of RLS especially in those patients who developed augmenta tion under L-dopa therapy. Owing to the remarkable therapeutic effect of pe rgolide on RLS symptom control, other dopamine agonists are presently being tested for the treatment of RLS. (C) 2000 Elsevier Science Ltd. All rights reserved.